The high rate of relapse is the most challenging issue in the treatment of cocaine and other drug addiction. The environmental stimuli associated with cocaine experience have been identified to be one main factor in triggering relapse. It is widely accepted that these conditioned stimuli (CSs) acquire motivational values through Pavlovian conditioning mechanisms and exposure to them even after a long period of abstinence can evoke powerful drug craving which drives drug-seeking behavior and ultimately, relapse. Attempts to use extinction procedures to reduce the motivation impact of such CSs have met a limited success. One reason is probably because the extinction-related paradigms used in animal studies are different from those used in clinic settings. In animal studies, extinction training is typically aimed to extinguish drug-seeking and drug- taking behavior (operant extinction) rather than the conditioned effects of drug CSs whereas in clinical settings, extinction training is aimed to extinguish the conditioned motivational effects of the CS (Pavlovian extinction) in the absence of the operant extinction. Such a disconnection severely hinders the translation of basic research into clinical treatments. To overcome this difficulty, this application proposes a novel animal model that can be used to specifically study the Pavlovian extinction. Recent advances in understanding the molecular mechanisms underlying the extinction process reignite the hope for the extinction-based treatment of drug addiction. One promising strategy is the combination of Pavlovian extinction training with drugs that can enhance the molecular signaling underlying the extinction memory. One goal of this application is to identify the receptor mechanism critically involved in the extinction process. Enhancing the function of such receptors may enhance the extinction memory that a CS is no longer associated with the drug and consequently, reduce the motivational impact of drug CSs on relapse. We will test the hypothesis that NMDA receptors in the infralimbic cortex (IL) play a critical role in consolidation of memory related to extinction of conditioned motivational effects of cocaine CSs. One distinctive feature of the proposed studies is that neuronal activity in the IL will be monitored in behaving rats. Simultaneous monitoring of neuronal activity and behavior provides a powerful tool to study the neuronal mechanisms of the behavior. In addition, by studying the effects of NMDA receptor antagonists and agonists microinjected into the IL on consolidation of extinction memory, we will identify the molecular mechanisms involved in this process. The results derived from this application will provide a basis for future translational studies to test the efficacy of NMDA receptor-related drugs in enhancing the effectiveness of the current extinction-based treatment for relapse. PUBLIC HEALTH RELEVANCE: Cocaine addiction is a public health issue and puts a heavy economic burden on society and family. The most difficult issue in treatment of this disease is the high rate of relapse. The long-term goal of the project is to understand the neural mechanism underlying extinction-mediated inhibition of relapse and such information will pave the way for development of effective drug treatments for this disease.